The cerebral cavernous malformation (CCM) is a common hemorrhagic vascular anomaly, presenting in sporadic and familial autosomal dominant forms, with three known gene loci. It affects more than a million Americans, predisposing them to a lifetime risk of stroke and epilepsy. There is currently no therapy to prevent the genesis or clinical progression of CCM lesions. Our group and others have implicated RhoA/ROCK signaling in vascular hyperpermeability central to CCM pathogenesis, and we developed murine models recapitulating the human disease. Our ongoing preclinical research has suggested ROCK activity as a biomarker of CCM disease severity, and its inhibition as potential therapy. We now propose an exploratory developmental project in human CCM patients, to translate observations from murine models that would suggest an exaggerated brain vascular leak in the familial form of the disease, and ROCK activity as a potential biomarker of this hyperpermeability. Our team has characterized a large cohort of human CCM patients, and we have implemented the tools to quantify human brain permeability using magnetic resonance dynamic contrast-enhanced quantitative perfusion (DCEQP) of gadolinium contrast agent, and to assess biomarkers of ROCK activity on peripheral blood leukocytes in patients. We hypothesize that vascular permeability is increased in the brain of patients with familial CCM disease who are heterozygous for one of the three CCM genes, that variances in this hyperpermeability among CCM patients reflect differences in disease severity, and correlate with ROCK activity in peripheral blood leukocytes. This research will validate practical novel tools of brain permeability and a blood bioassay as biomarkers of ROCK activity in CCM disease. In line with ongoing preclinical studies, our results will provide a further proof of concept in man. One or both techniques may be used in future research aimed at predicting and modifying CCM disease behavior in man and will likely help calibrate ROCK inhibition therapies in clinical trials. They will be applicable to other brain diseases where ROCK mediated hyperpermeability has been postulated as a central mechanism.